Analysis of the Acute Paroxysm

If we reflect on the general features and local characters of an initial outbreak of gout they are precisely such as would, did they occur anywhere but at the classic site, the big toe, suggest an infection. The abrupt onset, the local signs, the crisis, and no less the subsequent swift restoration to health, how strikingly reminiscent of an exanthematous fever! Moreover, does not this outward clinical resemblance seem to predicate an inward pathological similarity? And now to scrutinise more narrowly the component elements that make up the content of a paroxysm of gout.

Its fulminant onset, with shivering, if not a definite rigor, in a person in sound and sometimes exuberant health, irresistibly reminds one of the sudden onfall of an infective disorder. Doubtless, as Duckworth says, “the conditions leading up to the attack have been some time previously in operation.” But, as he rightly contends, “some determining factor must now be invoked to explain how, as it were, the train is fired.” Quite so, and what more likely to call into the open these latent morbid potentialities than an infection?

The constitutional disturbance is often profound, certainly out of all proportion to the severity and extent of the local phenomena. Especially prominent are the nervous concomitants—the excruciating pain, the irascibility, etc. Viewing these in light of the paroxysmal nature and periodicity of gout, Duckworth postulated a kinship between the disorder and the paroxysmal neuroses. But, given an infective element, what more plausible than to attribute the nervous phenomena of gout to the simultaneous action of its toxins on the higher centres?

The temperature curve, again, is obviously compatible with this conception. It begins abruptly, its course punctuated by daily remissions. No specific peculiarities apparently differentiate it from other arthritides of established or assumed infective origin, but its relatively low grade pyrexia recalls that typical of gonococcal arthritis. Its most striking feature, however, is the disproportion between the level of the pyrexia and the intensity of the general and local phenomena. Moreover, the temperature is not only low, but relatively ephemeral in duration, while the inflammatory reaction in its violence emulates that of the most sthenic forms of arthritis.

Albeit both the febrile disturbance and the local reaction display infinite grades of severity. Thus, acute gouty polyarthritis may be afebrile and the asthenic varieties of the affection marked by little inflammatory reaction. All these vagaries, however, are quite compatible with infection—the reflex, as it were, of varying degrees of toxæmia.

Says Duckworth, “The pyrexia proper to acute gout is paroxysmal with remission, and the pain of gout is likewise paroxysmal. One is reminded of the influence of marsh poison upon the nervous centres. This paroxysmal no less than periodic element in gout stamps a nervous character upon the malady and binds it in alliance with other well-recognised neuroses.”

How interesting these reflections by this distinguished physician in light of latter-day revelations! For, in so far as these features in gout are reminiscent of malaria, they disclose an affinity, not for a malady of nervous, but one of established infective, origin.

Simultaneously with the onset of pyrexia the pulse quickens. The blood shows that increase in fibrin characteristic of inflammation, a fact noted by Gulland, Cabot, Buchanan and others. But more significant is the presence of leucocytosis. It may be of high grade. In a case of acute gouty polyarthritis recently under my care the leucocyte count reached 27,000. Even in a subacute example of the classic monarticular type the leucocyte count attained 25,920. It was of leucoid type and attended by moderate anæmia due to deficiency of red corpuscles.

Nor is leucocytosis restricted to the periods of exacerbation, but it may be met with in the inter-paroxysmal stages. In my experience, even in cases of definitely chronic type it may reach 14,000. The higher grades of leucocytosis are obviously very suggestive of an infection, and that lesser degrees should be encountered in examples of definitely chronic type seems to point to gout being of the nature of a chronic or serial infection.

I would here add also that the converse of leucocytosis, viz., leucopenia, is sometimes met with in chronic cases. Dr. Munro and I have met with two instances of such in chronic gout in the intervals between paroxysms. This decrease in the number of leucocytes (leucopenia) is, of course, deeply interesting and, needless to say, quite compatible with infections, e.g., enteric, malaria, tuberculosis. In fact, it suggests that gout may be the outcome of divers infections, and not due to any specific organism.

Enlargement of the lymphatic glands was, by older authors, believed not to occur in gout. But obviously the lack of macroscopic evidence does not exclude the possibility of microscopic changes in these structures. The likelihood of such, moreover, is enhanced by the occasional occurrence of lymphangitis in connection with the inflammatory articular lesions. Buzzard, indeed, long since claimed that there was “clinical evidence of subacute gouty inflammation of lymph spaces in certain regions due to uratic deposit and influence.”

As a matter of fact, enlargement of the lymphatic glands does occur. Thus, my colleague James Lindsay cites an instance thereof. The subject, a painter, fifty-three years of age, had gout of some three years’ standing. During an acute paroxysm thereof “there was a mass of glands in the right groin, synchronous with an acute inflammation affecting the right knee and periarticular tissues. On the subsidence of the gouty inflammation the glands became smaller, but never entirely disappeared during the four weeks he was subsequently under observation.”

Splenic enlargement, states Duckworth, has been met with in many cases of gout, and occasionally infarcts. But such splenic enlargement is, he thinks, not specifically related to gout, but is due to associated conditions. Personally, I have not as yet met with splenic enlargement in gout.

This aside, is it not palpably significant of infection that Paget, Garrod, and others, repeatedly noted the incidence of acute phlebitis in a limb the seat of acute articular gout? Did we observe such a complication in any arthritis other than gouty, should we not inevitably regard it as indicative of the spread of an infection from the joint to the related veins?

Reverting to the local articular phenomena, they are not only compatible with, but emphatically suggestive of, an infective source. The typical signs of inflammatory reaction are swiftly installed in acute classical gout, and this with an intensity unrivalled save by the most sthenic types of acute arthritis. Witness how insistent were our forefathers, e.g., Scudamore, on the differentiation of acute gout, not so much from acute rheumatism as from erysipelas or phlegmon. Garrod, indeed, held that “if a medical man, by chance entirely ignorant of the nature of gout, were to see a toe affected by this disease in its full intensity, swollen, hot, red, and tender, he would probably think that the affection must of necessity terminate in suppuration, yet I believe this never happens as the result of simple gouty inflammation.” This leads us to note a salient feature of gouty inflammation, viz., it never results in pus formation. Now, allowing for the increased powers of discrimination that happily to-day are ours, is it not, I ask, significant that the disorders deemed most likely of confusion with acute gout belong to the frankly infective category?

That Garrod’s caveat was not uncalled for I feel sure, having myself known an acute gouty arthritis incised in the hope of evacuating pus. Sometimes the error in judgment is reversed and pyæmic or septic conditions in or near the great toe joint confounded with gout. Thus, Sir James Paget tells of an instance in which a pyæmic abscess forming near the great toe and consequent upon ligaturing of piles was thus confused. I recall, too, another example in which the supposed gouty arthritis of a great toe was of pyæmic nature, the outcome of a suppurating otitis media. Garrod, it may be recollected, ranked pyæmia as one of the disorders to which gouty subjects were especially liable.

Gouty inflammation resembles most other forms of the same morbid change, but some, however, contend that the association of œdema therewith is pathognomonic. Indeed, by some of the older authors this concomitant feature of gouty inflammation ranked as a criterion differentiating it from “true rheumatic inflammation.” Œdema, of course, is not distinctive of gouty as opposed to other forms of inflammation. But its occurrence therein is, we would submit, but another token of its affinity with the infective arthritides. We need but recall the constancy with which local œdema is met with in, e.g., gonococcal arthritis. More typical of gout, however, is the desquamation of the cuticule that follows the subsidence of the acute arthritis. Here we are reminded of the similar peeling of the skin that occurs in another infective disorder associated with arthritis, i.e., scarlatina.

Acute gout is definitely paroxysmal. The attack, at any rate when primary, is relatively ephemeral, lasts but a few days, and after it has passed, as Cullen says, “leaves the person in very perfect health, enjoying greater ease and alacrity in the functions of both body and mind than that for a long time before experienced.”

In short, acute gout would appear to be a self-delimited disease, its fleeting duration predicating that if an organism be responsible, the same is short-lived. Even in chronic gout, though it never quite loses its grip of those it has made its prey, yet nevertheless there are intervals of respite between the attacks, however long the latter may be. In other words, the disease never loses its paroxysmal character, which to my mind is very suggestive of a serial infection.

The periodicity of gout was, as we have seen, well known to the ancients. Its recurrence in early spring and late autumn has even been celebrated in verse:—

Scudamore referred its prevalence at these particular seasons to their attendant vicissitudes of heat and cold (the strongest of all the exciting causes of gout). Trousseau states that “gout with successive paroxysms shows itself early or late in the year, at the beginning of spring or late autumn, the wherefore I know not.”

This tendency on the part of acute gout to seasonal rhythm is ultimately lost. For, once the disorder is established, no period of the year confers absolute immunity. Whatever be the explanation of the vernal and autumnal incidence of gout in its early stages, this peculiarity is at any rate not incompatible with its infective origin. In this connection it may be recalled that it was once described as “a tertian fever terminating in fourteen days.”

Again, further evidence may be obtained from the action of colchicum, our sheet-anchor in the treatment of gout. Thus, Dixon and Malden have shown that colchicine has no action on the metabolism of purins or on the kidney. On the other hand, it causes a primary diminution followed by a marked increase in the number of leucocytes, which suggests the possibility that it exerts its beneficial effects by combating infection.

Lastly, turning our attention to the anatomical changes as disclosed after death during an acute articular paroxysm, these present appearances quite compatible with their infective origin. Dr. Munro, in one of my examples of acute gouty polyarthritis, aspirated the knee joint. The results of cytological examination were precisely such as are deemed characteristic of arthritides of infective source.

The results of our analysis of the component elements of an acute paroxysm of gout are, for the following reasons, strongly indicative of the intrusion of an infective element:—

The Evolution and Life History of Gout

If the onset, phenomena, and course of acute gout are reminiscent of infection, so, also, does a review of the life history of the disease, as a whole, carry with it the same inference.

For the course of gout, like other arthritides of chronic type, is not one of steady, uninterrupted progress, but one marked rather by periodic or intermittent advances, as if seemingly due to a series of successive infections or sub-infections. One is reminded of gonococcal arthritis in its more severe forms, the acute exacerbations which chequer its course being generally referred to intermittent absorption of fresh doses of the toxin from some smouldering infection in the prostatic urethra.

Now, if the general course or evolution of gouty arthritis is notably similar to that of the specific infective arthritides, so, also, do the clinical features approximate. Thus its onset, more often than not, is abrupt and attended by pyrexia of irregular or septic type, with an occasional leucocytosis.

Again, that not all cases of gout are of acute fulminant type may be admitted. We know that it may assume the guise of a fleeting arthralgia or “flying gout,” a transient synovitis, as well as an acute arthritis of mono-, oligo-, or poly-articular extent. This same polymorphism in respect of the joint lesions in gout is a replica of that met with in the specific infective arthritides. The milder varieties betokened by arthralgia or synovitis tend commonly to disappear, as it were, spontaneously in precisely the same manner as the arthralgias or synovites that follow the exanthemata, and we presume that, comparably with these latter, the source of infection dries up and restitutio ad integrum of more or less completeness follows.

But with repeated attacks, as in the specific infective arthritides, progressive infiltration and thickening of ligaments, capsule, and related tendinous and aponeurotic structures ensue. As far as these anatomical changes are concerned, gouty arthritis and the specific arthritides are at one, but with this outstanding difference, the associated uratic deposition. Save in respect of this last, the analogy is complete, and herein resides the specificity of gouty arthritis.

Chalmers Watson, from his observations of “gouty deposits” in human subjects in their relation to tendons, cartilage, and bone, came to the conclusion that the tout ensemble of the pathological lesions was very reminiscent of that typical of the more chronic types of infective disorders. Thus necrotic areas in gouty tendons stood in such clear relationship to the vascular supply as to suggest some infection viâ the blood-stream. Again, areas of erosion in the cartilage were found to be due, not to uric acid, but to the disintegrating action of small round cells of the nature of granulation tissue.

As to uratic deposits located in the bones, it was noted that their vicinity was characterised by marked vascularity, the existence of giant cells, and an accumulation of the small round cells so commonly correlated with the action of bacterial toxins.

In reviewing the foregoing clinical and pathological data and, alike, the inferences as to their significance, it cannot, we think, be gainsaid that, collectively, they are more readily explicable as being due to an infection than to any other morbid source.

Analogies between Gout and the Specific Infective Arthritides

A striking parallel can be drawn between the varied manifestations of gout and those met with in specific infections. But, to begin with, we must recall that our attitude towards infective disorders, e.g., acute rheumatism, gonorrhœa, etc., is altered in that we regard them now, not as local, but general, systemic infections.

Thus, following the revelations of bacteriologists, we now, for example, recognise that in gonococcal infection not only may there be articular involvement, but that muscular and nervous lesions may be associated therewith. This same, also, in acute articular rheumatism. True, its causal organism is still sub judice, but data accumulate as to the frequency with which the muscles are involved, and, to a less extent, the sheaths of nerves.

Take dysentery, again; it, too, as Sydenham pointed out, may be complicated, not only by arthritis, but by myalgias, while more recent experience emphasises the frequency with which neuralgias are associated therewith. In syphilis, also, the association of articular, muscular, and nerve lesions is well attested; and by French physicians it is insisted that, in tubercle, myalgias and neuralgias, as well as joint disorders, are infinitely more common than is generally realised.

To sum up, this triad of arthritic, muscular, and nerve lesions, either serially or simultaneously, is the most common complication of specific infections. Now, is not this same congeries of articular, muscular, and nerve disorders precisely the clinical content of gout?

Thus its articular manifestations constitute the most striking feature of the disease. As to the muscular troubles, there is a consensus of opinion as to their relative frequency. Inflammatory foci with associated uratic deposit have been found in muscles and tendons. We may here recall that the purin bases of the body exist, not only in the bound form (nucleic acid), but also free, especially in muscular tissue, also that from such free purin bases uric acid can be as readily formed as from those liberated by disruption of nucleic acid.

Clinically, one meets with all forms of fibrositis in actual association with acute articular gout. Such may affect either the neck, shoulder, loin, or sciatic nerve. In their work on “Fibrositis,” Bassett Jones and Llewellyn have shown that the disorder develops with significant frequency in the victims of gout. This but confirms the conviction held by Gowers, Garrod, Hilton Fagge, and others, viz., that the muscular and nervous types of fibrositis are frequently and obviously related to gout.

How noteworthy the well-established proclivity of gout to involve bursæ, tendon sheaths, and fasciæ, especially the plantar! Is not this exactly paralleled in certain infections? Note the predilection of post-scarlatinal rheumatism for bursæ and tendon sheaths; that of the gonococcus for these structures as well as fasciæ, not to mention the frequency with which bursal enlargements are traceable to syphilitic, tuberculous, and other infections.

We see, therefore, that in virtue of its tendency, not only to arthritic, but also to muscular and nerve disorders, gout falls into line with the specific infections. Its predilection for bursal and fascial structures is but another evidence of affinity with this group of disorders. In view of these similitudes, one may well ask, Are not these gouty manifestations, all of them, susceptible of a like explanation, viz., that they are the outcome of an infection?

For, in reviewing the foregoing analogies, it cannot, we think, be denied that in the aggregate they are emphatically suggestive of an infective origin.

Correlation of the Metabolic Phenomena of Gout with the Postulated Infective Element

In essaying this difficult task, we must recall to the mind of the reader our findings or deductions from the data disclosed in preceding chapters.

The outstanding conclusions that we felt justified in formulating were that:—

In other words, we suggest that, although abnormalities of metabolism form an integral part of gout, they are of themselves inadequate to achieve its efflorescence. Thus, when we came to consider the elemental manifestations of gout, i.e., uratic deposits or tophi, we saw that neither the purely physical nor the purely chemical theory of their origin would suffice, nor, for that matter, could any solution of this complex problem be gleaned from even a blend of the twain. In short, such hypotheses are too mechanical. The intrusion of some other factor, “some vital something biological,” seems essential for the elucidation of uratosis, i.e., uratic deposition. For this, not uricæmia, is the specific characteristic phenomenon of gout. If we cannot explain uratosis on physical or chemical grounds, then how much less, in view of the non-toxicity of uric acid, can we, on this basis, account for the inflammatory phenomena of the disorder?

Inflammatory reaction is, we hold, an invariable antecedent in all gouty processes, whether of articular or ab-articular site. Granted that inflammatory reaction is a necessary prelude, the specificity of gout is attested by the fact that this same is followed by the deposition of urates. But while the sequential uratic deposition invests all forms of “gouty” inflammation with a specific character, unshared by any other disease, it follows that the cause of the said inflammation must, if possible, be ascertained.

For Walker Hall “the contention that gout lowers the general tissue resistance, and so opens the way to bacterial infections, is so obvious that it need hardly be formulated.” In light of this, we need have the less diffidence in hazarding our opinion that the morbific agent responsible for “gouty” inflammation is an infection or sub-infection. Now, in all forms of arthritis other than gouty, the intrusion of a germ is held to be self-explanatory and final; in short, all the local morbid changes and constitutional disturbances are held satisfactorily accounted for by the organism or its toxins.

The problem of gout, however, is not so simple. Its arthritis is peculiar in that it is always accompanied or followed by uratic deposition, which, be it noted, is not an ordinary sequel of inflammation. It is, in short, the outcome of inflammation supervening in an individual of gouty diathesis. What do we know of this latter?

The researches of the bio-chemists reveal that uric acid is the end-product of nuclein metabolism—the summation of a long chain of enzymatic reactions. Some indeed have thought to find an adequate explanation of gout in enzymatic abnormalities. Thus, Adami and McCrae suggest that gout is the outcome of insufficient oxidation, whereby the precursors of uric acid and similar bodies are not fully oxidised, and, by their accumulation and toxicity, set up morbid changes, and the uric acid formed is, in its turn, imperfectly oxidised and accumulates. This diminished oxidation is due to a constitutional deficiency of oxydases, inherited or acquired.

This opens up the old problem as to whether uric acid is an intermediary or a terminal product of metabolism. But, from evidence cited in preceding chapters, it appears probable, if not certain, that uric acid is an end-product. Moreover, as Gideon Wells observes, “the failure of recent studies on the enzymatic transformation of purins to locate anywhere in the human body an enzyme-destroying uric acid makes hazardous the attempt to explain gouty metabolism as a result of enzymatic abnormalities.”

Indeed, in view of this, as hitherto ascertained, absence of uricolytic enzymes, there can, as Wells says, “be little doubt that the fundamental reason for the existence of uric acid gout in man lies in the inability of the human organism to destroy uric acid. Consequently, inasmuch as man, unlike other mammals, cannot destroy uric acid rapidly by oxidation, he is always a potential victim of uric acid retention and deposition.”

Now we have, we hope, shown that there is no evidence that the uric acid retention in gout is due to functional inability on the part of the kidney to excrete uric acid. This being so, we have, as Von Noorden rightly says, no right to do violence to the facts by assuming that, in a case lacking any other evidence of nephritis, a condition of “latent nephritis” is the cause of the uric acid retention and deposition.

Similarly, there is at present no evidence forthcoming that the retention of uric acid is due to abnormal purin combinations in the blood. Nay, according to Wells, on the best evidence obtainable, uric acid exists in a free state in the blood, and not combined, as has been urged by many workers in this sphere.

But if the cause of uric acid retention lies neither in the kidneys nor in the blood, there must exist something abnormal in the gouty individual which renders impossible what may be termed a compensatory uric acid excretion. Now, as disclosed in the previous chapter, experimental research, in diseases other than gout, has shown that the bodily tissues have an appreciable capacity for retention of uric acid (Fine). This, moreover, gains probability from the fact that Wiechowski, in his prolonged studies as to the possibility of uric acid decomposition in the human body, was never able to detect any evidence of uricolysis. Furthermore, on the clinical side, the fact that intravenous injection of uric acid does not produce a corresponding degree of uricæmia seems, as Bass and Herzberg suggest, to indicate that in gout the retention capacity of the tissues for uric acid is augmented. Lastly, in the precipitation and anchoring of urates in the tissues in gout, we have objective proof, i.e., tophi, that the uric acid is actually held in the tissues.

Does not this seem to indicate that there are peculiarities of tissue in the gouty? What, then, the subtle change that determines the retention and deposition of urates in the tissues in gout?

May we not, with Walker Hall, hazard the reflection that there may be differences between the nucleotides of normal and gouty tissues? For, doubtless, if there be peculiarities of tissue in the gouty, these will be reflected in abnormalities of tissue function and metamorphosis.

Gowlland Hopkins, discussing the metabolism of purins, holds that in gout there is some disturbance or defect in the fermentative functions of the tissues. Of a verity the range of intranuclear activities offers scope enough when we recollect that the cells of all tissues contain not only nucleinase, but also nucleotidase and nucleosidase. Even so, the resultant nucleins, the nucleotides, and nucleosides, have still further changes of deaminisation and oxidation to undergo, these carried out in the liver and elsewhere!

We may talk of defects in the enzymatic functions of the tissues, but, viewing gout clinically, and more particularly the hypersensitiveness of its victims to the most varied stimuli, dietetic and other, one inclines rather to predicate in their instance an inherent instability of nuclein metabolism. For in the gouty, as Walker Hall observes, “a slight injury or indiscretion of diet, an overloaded intestine, or increased toxicity of the intestinal flora, may be followed by a disturbance of the general nuclein metabolism, and a local reaction in certain tissues.”

With this pronouncement all clinicians will be in accord, and herein, too, we may, I think, discern how the latent tissue idiosyncrasies of the gouty are evoked, i.e., by infection; in other words, that, under the influence of these morbific agents, the innate morbid potentialities of the gouty become overt and manifest.

The exact modus operandi whereby the assumed organisms or their toxins determine the efflorescence of gout is uncertain. We know that, following the intake even of non-purin-containing foodstuffs, an increase in uric acid excretion ensues, and that the same is the outcome of the stimulation of general nuclein metabolism. Is it not conceivable that the responsible toxin acts in like fashion, and haply by disturbing the orderly sequence of those exquisitely delicate enzymatic reactions which culminate in the formation of uric acid, and with which potentialities every living cell in the organism is dowered? Further than this we, pending future researches by the bio-chemists, may not go, for “the positive material is much too insufficient, and much too ambiguous.”

In conclusion, I would postulate that in gouty subjects:—